The male sexual response includes the filling of vascular channels that are empty in the flaccid penis, with blood at pressures approaching systemic levels. Erection occurs when the arteriolar and sinusoidal smooth muscles of the vessels within the corpora relax, thus lowering resistance in these channels and allowing arterial blood to surge into the penis. Exit of the arterial blood is simultaneously impeded by an increase in venous resistance. Further distention of the sinusoids is restrained by the minimally distensible tunica albuginea that raises the pressure further and also restricts venous outflow. Thus, the corpora cavernosa and corpus spongiosum can be filled with blood and the penis can be erect with little demand on cardiac output. These vascular changes that occur during erection are thought to be controlled by vasoactive intestinal polypeptide, perhaps aided by alpha-adrenergic blockade, acetylcholine and nitric oxide.
The female sexual response cycle is typically divided into four phases including desire, excitement, which includes physiological changes such as vasocongestion in the pelvis, vaginal lubrication, and expansion and swelling of the external genitalia, orgasm, and resolution. Disorders of female sexual desire or response are estimated to affect from 30 to 50 percent of the adult female population. These disorders may have a variety of causes including psychogenic etiologies, anatomical disorders, drug-induced disorders, diabetes mellitus, post-surgical disorders, atherosclerosis, post-traumatic disorders, as well as endocrine etiologies. Depending upon the etiology of the disorder, effective treatment may be had by overcoming any boundaries to the physiological changes that take place during excitement including vasocongestion. Thus, in certain cases, it may be possible to enhance the female sexual response by stimulating vasocongestion.
There are a wide variety of pharmacological agents used for the enhancement of erection and treatment of sexual dysfunction and as pro-libido agents. Some examples include: serotonin receptor agonists and antagonists (see, e.g., EP 385,658; WO 94/15,920; GB 2,248,449; and GB 2,276,165), dopamine receptor agonists (see, e.g., WO 93/23,035; WO 94/21,608; Pomerantz S. M., Pharmacol. Biochem. Behav. 39:123–128, 1991; and Ferrari F. et al. Psychopharmacology 113:172–176, 1993); adrenergic receptor agonists (see, e.g., WO 95/13,072; EP 611,248; U.S. Pat. No. 5,229,387; and WO 92/11,851); inhibitors of phoshodiesterase (see, e.g., DE 4,338,948; and WO 94/28,902); histamine receptor agonists (see, e.g., U.S. Pat. Nos. 4,013,659; 4,126,670; 4,767,778; WO 91/17,146; U.S. Pat. No. 5,047,418; and EP 0,458,661); neuropeptide Y antagonists (see, e.g., WO 95/00,161); angiotensin II receptor antagonists (see, e.g., EP 577,025); cholinesterase inhibitors (see, e.g., U.S. Pat. Nos. 5,177,070; and 4,633,318); combinations of agents with the different types of biological activity (see, e.g., U.S. Pat. No. 5,145,852; and WO 95/05,188); derivatives of vasoactive intestinal peptide (see, e.g., U.S. Pat. No. 5,147,855; EP 540,969; and EP 463,450); prostaglandins (see, e.g., WO 93/00,894; and EP 459,3770); antidepressants and antipsychotics (see, e.g., U.S. Pat. No. 4,931,445; GB 2,448,449; and Naganuma et al. Clin. Exp. Pharm. Physiol. 20:177–183, 1993); nitric oxide donors (see, e.g., WO 92/21,346; DE 4,305,881; DE 4,212,582; and WO 94/16,729); calcitonin gene related peptide (see, e.g., Steif, C.G. et al., Urology, 41:397–400, 1993); and androgens (see, e.g., JP 06,211,675; HU 62,473; and WO 94/16,709). Unfortunately, many or all of these pharmacological agents are associated with adverse effects including aggravation or induction of schizophrenia, serotonin syndrome, central nervous system and endocrine system dysfunction, pain, echytomosis and priapism.
Accordingly there is a need in the art to identify new pharmacological agents or compositions which are useful for enhancement of the sexual response in mammals.